Constent statement:
Written informed consent was obtained from the parents(minor patient)
prior to study inclusion according to the local ethical regulations.
Abstract:Introduction: Osteogenesis
Imperfecta (OI) is a rare genetic disorder characterized by increased
bone fragility and recurrent fractures. OI is classified into types I-IV
based on clinical features, with the majority of cases attributed to
mutations in the COL1A1 and COL1A2 genes encoding type I collagen.Case Presentation: Here we present the case of a newborn with
OI who exhibited widened fontanelles and short limbs. Genetic testing of
the patient and parents was conducted, with validation by Sanger
sequencing. At five months, comprehensive imaging studies were performed
to observe skeletal development. A novel missense mutation
(c.4097T>A) was identified in the COL1A1 gene of the
patient; however, neither the mother nor father carried this mutation.
At five months, the child exhibited lower height and weight than normal
infants, along with shortened limbs. Radiographic examination revealed
slender limb bones and reduced bone density. Based on the clinical
presentation and genetic testing, a diagnosis of type IV Osteogenesis
Imperfecta (OI) was established. Conclusion: Overall, in this
case we present a new mutation site
(c.4097T>A; p.Ile1366Asn) in COL1A1 in a patient with OI.
This mutation suggests a potential link to Type IV OI in the Chinese
population, and this case contributes to the diversity of
COL1A1 pathogenic mutations.Keywords Type IV OI; Type I collagen; COL1A1 gene; novel
mutation.
Introduction
Osteogenesis Imperfecta (OI) is a hereditary disorder characterized by
fragile and deformed bones, recurrent fractures, blue sclera, incomplete
tooth development, short stature, and progressive hearing loss. More
than 90% of OI cases result from mutations in the genes COL1A1 and
COL1A2, which encode Type I collagen, and the inheritance pattern is
typically autosomal dominant. The prevalence of OI is extremely low,
estimated to be approximately 1 in 15,000-20,000
individuals[1]. In Europe and the United States,
the reported birth prevalence ranges from
3-7/100,000[2-3], whereas in Finland,
approximately 0.5/10,000 people are affected[4].
OI is categorized into four types based on the severity of clinical
manifestations, as follows: Type I (mild), Type II (lethal), Type III
(severe deformities), and Type IV (moderate deformities), with Type I
being the most common[5-6]. Statistical data on
the prevalence of OI in the Chinese population are currently lacking.
However, according to Li et al.[7], among 668
patients with OI from 378 Chinese families, Type I accounted for 39%,
and Type IV accounted for 35% of cases. Here we present the case of a
newborn diagnosed with OI ultimately confirmed as Type IV, and detail
the diagnostic and therapeutic processes based on genetic testing and
clinical observations.
Case History and Examination
The patient was a female infant with the chief complaint of premature
rupture of the membranes at 26 h, born after 37 min of labor, with a
birth weight of 2500 g. Physical examination revealed a head
circumference of 32 cm, noticeable widening of the anterior fontanelle,
and a sagittal suture with a maximum width of 4.5 cm. Other findings
included white sclera, multiple missing teeth in both the upper and
lower jaws, outward expansion of the bilateral rib cage, no apparent
spinal deformities, short limbs, and wrinkled skin on the palms and
soles.
Based on the patient’s clinical presentation of the newborn, OI was
suspected. Targeted high-throughput sequencing was employed to conduct
genetic testing on the patient and her parents, identifying a
heterozygous, potentially pathogenic variant of the COL1A1 gene,
specifically c.4097T>A (p.Ile1366Asn), which correlated
strongly with the patient’s clinical phenotype (Table 1). The mutation
site was verified by Sanger sequencing, while First-generation Sanger
sequencing indicated that the parents did not carry the COL1A1
c.4097T>A mutation (Figure 1) .
Upon a follow-up visit at 5 months of age, the patient exhibited slower
growth than normal infants. Her weight was 3000 g, height was 60 cm, and
the sagittal suture of the skull was approximately 4cm wide with a
grayish-white sclera. The spine showed no signs of lateral deformity and
the limbs were relatively short. Radiographic examination revealed
thinning of the bilateral humerus, radius, femur, and tibia-fibula
bones; slight curvature of the radius and ulna; and underdeveloped and
shallow hips on both sides (Figure2) .
Methods
Differential diagnosis
OI needs to be differentiated from Osteopetrosis and
Osteoporosis[8-9].
Osteopetrosis: Osteopetrosis is a rare metabolic bone disease
characterized by widespread calcification of the entire skeletal
system and thickening of bone cortices.
Osteoporosis: Osteoporosis is a common metabolic bone disease
characterized by decreased bone mass and microstructural damage to
bone tissue, leading to bone fragility and susceptibility to
fractures. X-rays of osteoporosis patients may show reduced bone
mass and blurred trabeculae, which resemble the X-ray features of
osteogenesis imperfecta. However, osteoporosis patients typically
have a negative family history.